Liquid-suspension controlled-release pharmaceutical composition

ABSTRACT

Disclosed is a liquid-suspension controlled-release enteric-coated pharmaceutical formulation for the administration of naproxen, comprising (a) microgranules of naproxen and an excipient; (b) four successive coats of polymeric hydrophilic and hydrophobic materials, at least the innermost of said coats imparting controlled-release properties to said naproxen according to a predetermined release profile, and at least the outermost of said coats imparting resistance to dissolution in gastric fluids; and (c) a liquid administration vehicle. This composition enables the oral administration of naproxen as a single daily dose the adjustment of the dosage to a patient&#39;s requirements, and avoids detrimental effects of prolonged contact of naproxen with the gastric mucosa thus aiding oral intake and minimizing the drug&#39;s typical side effects.

This application is a division of U.S. Ser. No. 08/165,307, filed Dec.10, 1993, now U.S. Pat. No. 5,527,545, which is a continuation-in-partof U.S. Ser. No. 07/928,616, filed Aug. 10, 1992, now U.S. Pat. No.5,296,236, which is a continuation of U.S. Ser. No. 07/711,588, filedJun. 6, 1991, now abandoned, which is a continuation of U.S. Ser. No.07/408,755, filed Sep. 18, 1989, now abandoned.

FIELD OF THE INVENTION

The invention involves controlled-release pharmaceutical formulations inliquid dosage forms for the administration of naproxen.

BACKGROUND OF THE INVENTION

(S)-6-methoxy-α-methyl-2-napthaleneacetic acid (naproxen) is along-known non-steroid anti-inflammatory drug, which also has analgesicand antipyretic activity (U.S. Pat. No. 3,904,682 and U.S. Pat. No.4,009,197).

Because of the anti-inflammatory and analgesic activities of naproxen,it is indicated for treating various forms of arthritis, such asrheumatoid arthritis, osteoarthritis, ankylosing spondylitis, and goutarthropathy; as well as for treating forms of extraarticular rheumatism,such as lumbar sciatica, myalgia, neuralgia, radicular syndromes,periarthritis, myofibrositis and the like.

Therapy generally involves the use of daily doses ranging from 250 mg to1,000 mg of active ingredient and the formulations currently availablefor administration include tablets, capsules, granules for extemporesuspension (oral route), suppositories (rectal route), vials(intramuscular route), gels and emulsions (topical route). All theseformulations are essentially designed to make the active ingredientreadily available in the body in order to ensure a rapid onset of thetherapeutic effect.

In particular, with respect to the oral administration route, the wishto extend the duration of the therapeutic effect led to the developmentof controlled drug release formulations to enable a single dailyadministration. It is in fact known that once-daily administrationenables better patient compliance with recommended dosages duringtherapeutic treatment. For instance, patient compliance is reported tovary from 87% for drugs taken once a day to 39% for drugs taken fourtimes a day (J. A. Cramer et al., JAMA It. ed. 1, 601 (1989)).

Examples of formulations suitable for once-daily administration arereported in U.S. Pat. No. 4,803,079, which describes the use of a matrixin which the active ingredient is dispersed and released by diffusion,as well as in European Patent Application EP 438,249 which describes theuse of slow release pellets for the administration of a delayed releasedose together with a ready release dose; and in European Patent EP250,374, which describes solid dosing units suitable for the controlledrelease of drugs, including naproxen, with zero order kinetics.

The main drawback of all of these applications is the final large sizeand high weight of the solid dosage unit. This is particularly true ofdosages with a high active ingredient content (as is the case withnaproxen). Thus, for instance, by applying the teachings of U.S. Pat.No. 4,803,079, a tablet containing 1,000 mg of active ingredient wouldhave an overall weight of about 1,300 mg, a diameter of about 15 mm, anda thickness of about 7 mm.

Obviously, administration of a dosage unit with these dimensions andweight to patients with difficulty swallowing presents a problem. Thisis not a minor problem considering that, for the above types ofdiseases, the patient population that uses naproxen is generally made upof elderly individuals.

Even when the formulation is broken down into micro-units (granules orpellets), the need to avoid overdosing (which in the case of naproxenmay induce torpor, heartburn, dyspepsia, nausea or vomiting) requiresthat the micro-units be enveloped in a container (e.g. a gelatinecapsule). The container will have dimensions similar to the ones above,and, therefore, will not avoid swallowing problems.

A further disadvantage of the oral administration of solidcontrolled-release dosage forms in the case of naproxen is that theactive ingredient carried either in a tablet or in a capsule may causelocal gastrointestinal contact intolerance which may occasionally causebleeding in the gastrointestinal tract, peptic ulcer or colitis.

The concentration of naproxen reaching a gut mucosal cell depends bothupon the drug's concentration in the lumen of the gut and the plasmaconcentration of the drug in mucosal capillaries.

It is generally believed that the mucus barrier in patients susceptibleto gastrointestinal contact intolerance is somewhat deficient. Naproxenpenetrates this barrier, inhibits the formation of the prostaglandinsthat sustain the mucus barrier and thereby allows hydrogen ions from thegastric lumen to penetrate and damage the mucosa.

This phenomenon leads to a need for a drug formulation that would avoidthe problems of dispersion and topical contact with the gastric andupper duodenal mucosa. In principle, these problems can be avoided byusing an "enteric" coating, i.e. one that is stable at low pH anddissolves at a higher pH (defined in Remington's Pharmaceutical Science,18th Ed., pages 1669-1679).

One solution to the problems caused by solid controlled-release dosageforms is to use liquid-suspension controlled-release formulations. To beeffective, they must be particularly homogeneous, suspendable andpalatable as well in a form that guarantees the required releaseprofile, and must therefore be made up of particles of sizes andcharacteristics that will allow the above requirements to be met.

Generally, the requirement for such small dimensions means keeping theexcipient quantity ratio low in order to preserve the ability of theformulation to remain in suspension and to avoid a "sand-like" sensationupon ingestion. It is also particularly important to maintain a highconcentration of active ingredient in the microgranules when treatmentconditions require a high dosage, as is the case with naproxen.

For instance, in the formulations described in the international patentapplication WO 89/8448, the enteric-coated granules have diameterslarger than 0.5 mm and, therefore, are totally unsuitable for suspensionin liquid formulations.

Examples of formulations dimensionally suitable for liquid suspensionfor the administration of naproxen are described in the Belgian patentBE 903,540, which claims a powder controlled-release compositionconsisting of particles of sizes ranging from 0.1 to 125 μm that aresaid to be suitable for the liquid administration of several drugs,including naproxen.

Copending commonly assigned U.S. patent application Ser. No. 928,616(corresponding to EP 359,195) also describes a therapeutic system forliquid controlled-release pharmaceutical compositions that can be usedto administer naproxen. This system consists of microgranules coatedfirst with a pH-insensitive (inner most) coating that imparts controlledrelease properties to the microgranules, followed by various alternatecoats of lipophilic and hydrophilic materials so that the total size ofthe microgranules ranges from 50 to 500 μm. The microgranules formstable suspensions in liquid administration vehicles.

However, by applying the teachings of the foregoing third party patentsand applications, no liquid suspension naproxen-containing formulationshave been developed that are capable of achieving therapeuticallyeffective naproxen levels by a single daily administration. Furthermore,none of the liquid formulations described in the above patentapplications is designed to get through the gastric fluid barrier. Inaddition, the foregoing copending U.S. patent application Ser. No.928,616 does not specifically disclose a liquid controlled releaseformulation for naproxen suitable for a once-a-day administration nor anaproxen containing liquid formulation capable of withstanding gastricfluid.

It is thus an object of the present invention to provide acontrolled-release pharmaceutical dosage form in liquid suspensiondelivering therapeutic levels of naproxen in the blood stream of apatent with a single daily administration, while avoiding thedetrimental effects of prolonged contact of naproxen with the gastricmucous membrane.

SUMMARY OF THE INVENTION

It has now been found that a controlled-release pharmaceutical dosageform suitable for a once-daily administration of naproxen in a liquidsuspension can be achieved using a multiplicity of microgranulescontaining naproxen as an active ingredient, which are coated with aseries of successive coatings comprising:

a first coating applied directly to the microgranules that impartscontrolled-release properties and contains polyethylene glycol as oneingredient;

a second coating applied to the first coating and having hydrophiliccharacteristics

a third coating applied to the second coating and having lipophiliccharacteristics, and

a fourth outermost coating having hydrophilic characteristics andcontaining cellulose acetate phthalate (CAP) or another polymer orpolymers having the property of forming enteric coatings. The outermostcoating imparts resistance to dissolution of naproxen in gastric fluids.Preferably, the total number of coatings is four.

The coated microgranules, which after coating have sizes ranging fromabout 50 to about 500 μm, are preferably combined with such optionalingredients as suspending, sweetening, buffering, preserving, orflavoring agents, or mixtures thereof. They can then be suspended inwater or other physiologically acceptable mediums to obtain a liquiddosage form. Dosages can be adjusted by administering different amountsof the final liquid dosage form.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing simulated steady state blood levels ofnaproxen over five days after once a day administrations of naproxen.

DETAILED DESCRIPTION OF THE INVENTION

The disclosure of U.S. patent application Ser. No. 928,616 is herebyincorporated by reference in its entirety.

The composition of the present invention comprises a multiplicity ofmicrogranules comprising a mixture of naproxen and excipients and havinghomogeneously smooth surfaces that permit uniform disposition ofcoatings (e.g., substantially spherical surfaces). The microgranules arepreferably prepared as disclosed in copending patent application Ser.No. 928,616 and are then coated. The series of four coatingssequentially applied one on top of the other that may comprise forexample (i) ethylcellulose plus plasticizer and polyethylene glycol;(ii) cellulose acetate phtalate and plasticizer; (iii) one or more waxesand (iv) cellulose acetate phtalate and plasticizer.

This formulation thus preserves the release characteristics of thedosage forms that are carried in it. It can be designed either as aliquid dosage formulation that remains stable for a relatively longperiod of time, or as a dry formulation that is reconstituted with waterwhen needed and then remains stable throughout the period of treatment.

Since a significant improvement in patient compliance can be achieved bythe present invention, its advantages in terms of reducing the number ofdaily doses while being convenient to administer and to swallow areclear. Additionally, an improved therapeutic response can be expected asthe dosage can be adjusted to individual requirements simply bymeasuring the required suspension volumes. Finally, the outermostcoating enhances local gastrointestinal contact tolerance, thus reducingundesirable side effects.

In detail, in a preferred embodiment, the present invention comprises aliquid measurable enteric-coated controlled-release pharmaceuticalcomposition that includes:

1) Dosage forms for the controlled release of naproxen having sizesranging after coating between 50 and 500 μm (preferably 90 and 300 μm),capable of remaining easily in suspension in a liquid for prolongedperiods of time, each of said forms comprising:

a) a mixture of naproxen and excipients treated so as to formmicrogranular cores of small size, substantially uniform surface,lacking sharp or discontinuous morphology and permitting depositions ofuniform coatings thereon to ensure reproducibility and uniformdistribution of the successive coatings;

b) a first coating in contact with said microgranular cores impartingcontrolled release properties to the naproxen contained in the core,said coating containing polyethylene glycol;

c) a second hydrophilic coating on top of the first coating;

d) a third lipophilic coating on top of the second coating;

e) a final outer coating with "enteric" characteristics, meaning that itresists dissolution in gastric fluids but disintegrates in the smallintestine. The last coating contains an enteric coating forming polymer(such as CAP) and if appropriate a plasticizer.

2) A vehicle system for the above controlled-release forms comprisingeither:

a) a dry mixture of suspending agents, sweetening agents and thecontrolled-release forms described in 1), a formulation that can bereconstituted into a liquid dosage form by suspension in an aqueousmedium when needed; or

b) an aqueous solution of the above suspending and sweetening agents inwhich the controlled release forms described in 1) can be suspended andmaintained in optimum release conditions for extended periods of time.

In accordance with the present invention it has now been found thatgranules with a high content of active ingredient (more than 50% andpreferably 80-90% by weight), uniform surfaces, preferably almostspherical shapes, apparent densities ranging between 300 and 800 g/l(preferably 500-600 g/l) and very low friabilities, can be obtained bywet-mixing naproxen and excipients by known techniques described in U.S.patent application Ser. No. 928,616 and EP 359,195.

The microgranulate is then evaluated for particle size distribution anddensity. This allows the calculation of the surface area of themicrogranulate (as described below), which in turn allows the depositionof a reproducible and uniform amount of coating on the microgranules.

By mathematical processing of the particle size distribution data, thed_(g) (mean geometric diameter) and σ_(g) (standard deviation) ofparticle size distribution are calculated. Then d_(vs) is calculated asfollows from d_(g) and σ_(g) : log d_(vs) =log d_(g) -1.151 log² σ_(g),where d_(vs) is the diameter volume-surface.

The surface area is then derived by means of the following formula:surface area=6/P_(g).d_(vs) wherein P_(g) is the apparent density.

By knowing the surface area, it is then possible to apply a constantamount of coating on the microgranules since a given coating amount (ing/m²) is directly proportional to the surface area. After coating, themicrogranules have a size within the range of 50-500 μm, preferably90-300 μm. It should be noted, however, that coating does notsubstantially affect the size of the microgranules.

Examples of the elements that comprise the pharmaceutical formulation ofthe present invention are described below without limitation:

Microgranular cores--1 a):

The excipients used to make the cores can be chosen from those commonlyused in wet mixing, such as dibasic calcium phosphate, lactose,microcrystalline cellulose, starch, talc, sugars, polyvinylpyrrolidone,polyvinylpyrrolidone/vinyl acetate copolymer and the like. The mixingliquid can be water or a solvent that can be mixed with water such as,for instance, ethyl alcohol or other commonly used alcohols, or amixture of water and alcohol.

In accordance with the present invention, the granulate is then coatedin successive stages with coatings of different compositions, usingknown coating techniques. Nonlimiting examples of each type of coatingare given below:

Coating that Controls Release--1 b):

A cellulose derivative capable of imparting release controlcharacteristics, such as ethyl cellulose is mixed with a plasticizersuch as diethyl phthalate (in an amount within the range of 10-30% byweight of the total mixture exclusive of solvents) in the presence ofpolyethylene glycol. The plasticizer may be omitted if water is used asthe solvent.

The addition of 0.1-5% polyethylene glycol to the coating mixtureimparts to the coating responsible for controlling release additionalhydrophilic properties that enhance the diffusion of poorlywater-soluble substances such as naproxen.

Hydrophilic coating--1 c):

Hydrophilic substances such as methyl cellulose, methacrylic acidcopolymers, or polyvinylpyrrolidone may be used for this coating.

Lipophilic coating--1 d):

Fatty substances such as mono-, di- or triglycerides of fatty acidshaving 6 to 32 carbon atom chains, carnauba wax, beeswax, candelillawax, fatty alcohols, and fatty acids may be used for this coating.

Enteric Coating--1 e):

The same substances that make up this coating 1 e) may also be used asingredients for the second (hydrophilic) coating 1 c). The outermostenteric coating contains cellulose acetate phthalate (or another polymeror polymers having the property of forming enteric coatings) and aplasticizer. See, Remington, supra, and USP XXII 724, p. 1580-81, 1990.

Plasticizers are preferably added to type 1 c) as well as to type 1 e)coating materials. The choice of a plasticizer for these coatingsdepends on whether it will be used for a wet process or for a processthat uses organic solvents. (As stated above, plasticizer is notnecessary when water is the only solvent.) Chlorinated solvents such aschloroform, alcohols such as ethanol, methanol or isopropyl alcohol,ketones such as acetone or methyl ethyl ketone, and different mixturesof the above solvents can be used as coating solvents instead of water.Mixtures of water and one or more water-miscible organic solvents canalso be used.

Plasticizers that can be used include without limitation diethylphthalate, dibutyl sebacate, triacetin, trialkylcitrate, vegetable oil,acetylated glycerides, polyethylene glycol or propylene glycol. Choiceof plasticizer is within the skill in the art. The preferred plasticizerfor use in the present invention is diethyl phthalate. The amount ofplasticizer that is used varies with the coating substance and is withinthe skill in the art. Generally, the plasticizer comprises 10-30% (w/w)of the total polymeric mixture exclusive of solvents.

Vehicle--2 a) and 2 b):

The granulate coated according to the above procedures is then combinedwith a vehicle to form either a solid mixture that can be suspendedextempore when needed or a suspension ready for use.

In addition to the coated microgranules comprising controlled-releasedosage forms of the active ingredient, the ingredients which make up thevehicle are:

suspending and bodying agents such as cellulose esters, microcrystallinecellulose, alginic acid derivatives, and polyvinylpyrrolidonederivatives;

sugars such as sucrose and sorbitol;

buffering agents such as citric acid and sodium nitrate, glycine andhydrochloric acid, sodium and potassium phosphates;

preservatives and bacteriostatic agents such as p-hydroxybenzoic acidesters; and

various flavorings and sweeteners commonly used in pharmaceuticals.

In addition to the above ingredients, the formulation includes water ormixtures of water and co-solvents such as a glycol, an alcohol, andglycerin.

The methods, tables and examples provided below are intended to morefully describe preferred embodiments of the invention and to demonstrateits advantages and applicability without limiting its scope.

EXAMPLE 1

Preparation of the Microgranulate

A mixture made up of 3,200 g naproxen, 400 g polyvinylpyrrolidone and400 g lactose was mixed for 5 minutes so as to ensure good homogeneity.500 ml of water atomized at a 2 bar pressure were then added to themixture under stirring at a flow rate of 35 ml/min. The granulate wasmade spheroidal by stirring the mixture for an additional 10 minutes.The spheroidal product was then dried for about 2 hours on atemperature-controlled static bed at 35° C. until the residual humiditywas reduced to a level of 4-5% by weight. The spheroidal product wassieved through 0.6 mm sieves until a granulate with a size range of 90to 300 μm and a spheroidal shape with no particular surface roughness orunevenness was obtained.

EXAMPLE 2

500 ml of atomized water at a 15 ml/min flow rate and a 2 bar pressurewere added to a mixture made up of 3,560 g naproxen and 440 gpolyvinylpyrrolidone and mixed as described in Example 1. The granulatewas then made spheroidal, dried and sieved as described above.

EXAMPLE 3

450 ml of atomized water at a 20 ml/min flow rate and a 2 bar pressurewere added to a mixture made up of 3,200 g naproxen, 400 gpolyvinylpyrrolidone and 400 g dibasic calcium phosphate dihydrate andmixed as described in Example 1. The granulate was then made spheroidal,dried and sieved as previously described.

EXAMPLE 4

500 ml of atomized water at a 15 ml/min flow rate and a 2 bar pressurewere added to a mixture made up of 3,200 g naproxen, 400 gpolyvinylpyrrolidone, 200 g lactose and 200 g dibasic calcium phosphatedihydrate mixed as described in Example 1. The granulate was then madespheroidal, dried and sieved as previously described.

In general, the preferred mean geometric diameters for the uncoatedmicrogranules are within the range of 120-200 μm (most preferred:130-170 μm) with a standard deviation of 1.4-2.0 (most preferred:1.5-1.8). The preferred apparent density is 1.2-1.5 g/ml (most preferred0.5-0.66 g/ml) and packed density is 0.5-0.9 g/ml (most preferred:0.55-0.8 g/ml).

The formulations that can be used for the successive coatings aredescribed in succeeding Examples, as follows: First coating (examples5-7); second coating (examples 8-10); third Coating (examples 11-15);and fourth coating (Examples 16-18).

EXAMPLE 5

Coating of Microgranulate

First Coating in Contact with Core

500 g of microgranulate prepared as in Example 1 were introduced into afluid-bed coating apparatus, into which air heated to a temperature of40°-45° C. was blown at a rate of 40-45 m³ /hour, and turbulence stirredfor 1 minute. The microgranulate was sprayed, at a 2 bar pressure and a16 g/min flow rate, with a solution having the following percentcomposition by weight:

    ______________________________________                                        Ethyl cellulose  3.00                                                         Diethyl phthalate                                                                              1.00                                                         Polyethylene glycol                                                                            0.10                                                         Ethyl alcohol    21.35                                                        Chloroform       74.55                                                        ______________________________________                                    

The quantity of material used to achieve a given coating thickness isdependent on the total surface area of the granulate to be coated. Forexample: 585 g of the above solution are sprayed to obtain 1.6 g/m²coating, whereas 731 g of the same are necessary to obtain 2.0 g/m²coating. Surface area can be determined as described above. The coatingthickness is selected for the most favorable dissolution profile byroutine experimentation. Once selected, the optimum coating thickness iskept constant.

EXAMPLE 6

Following an operating procedure identical to that described in Example5, the microgranulate may be coated with a solution having the followingpercent composition by weight:

    ______________________________________                                        Ethyl cellulose  2.5                                                          Diethyl phthalate                                                                              1.0                                                          Polyethylene glycol                                                                            0.2                                                          Ethyl alcohol    96.3                                                         ______________________________________                                    

EXAMPLE 7

Following an operating procedure identical to that described in Example5, the microgranulate may be coated with a solution having the followingpercent composition by weight:

    ______________________________________                                               Ethyl cellulose                                                                         3.0                                                                 Diethyl phthalate                                                                       1.0                                                                 Ethyl alcohol                                                                           21.0                                                                Chloroform                                                                              75.0                                                         ______________________________________                                    

EXAMPLE 8

Second Coating (Hydrophilic Coating)

The same operating procedure described in Example 5 for applying thefirst coating was also used to apply the hydrophilic coating. A solutionhaving the following percent composition was applied at a 2 bar pressureand an 8-10 g/min flow rate:

    ______________________________________                                        Methacrylic acid copolymer                                                                       12.5                                                       (Eudragit E ®)                                                            Acetone            35.0                                                       Isopropyl alcohol  52.5                                                       ______________________________________                                    

The amount of solution used for the second coating depends upon theamount used for the first coating. For example, 155 g of the abovesolution are used when 1.6 g/m² of the first coating is applied, whereas196 g of the same are necessary when 2.0 g/m² is used.

EXAMPLE 9

Alternatively, the solution used to apply the second coating maycomprise the following percent composition by weight:

    ______________________________________                                               Methylcellulose                                                                         3.0                                                                 Water     97.0                                                         ______________________________________                                    

EXAMPLE 10

Another solution suitable for the second coating layer has the followingpercent composition by weight:

    ______________________________________                                        Polyvinylpyrrolidone                                                                            5.0                                                         Water             95.0                                                        ______________________________________                                    

EXAMPLE 11

Third Coating (Lipophilic Coating)

A solution having the following percent composition by weight wasapplied to the second coating using the same pressure and flowconditions described in Example 5:

    ______________________________________                                        Glyceryl monostearate                                                                           4.50                                                        White beeswax     0.40                                                        Cetyl alcohol     0.05                                                        Stearyl alcohol   0.05                                                        Chloroform        89.60                                                       Methanol          5.40                                                        ______________________________________                                    

The amount of solution used for the third coating depends upon theamount used for the first coating. For example, 577 g of the abovesolution are used when 1.6 g/m² of the first coating is applied, whereas697 g of the same are necessary when 2.0 g/m² is used.

EXAMPLE 12

Alternatively, the third coating may be achieved using a solution havingthe following percent composition by weight:

    ______________________________________                                        Glyceryl monostearate                                                                           6.5                                                         Chloroform        93.5                                                        ______________________________________                                    

EXAMPLE 13

An alternative solution suitable for the third coating layer has thefollowing percent composition by weight:

    ______________________________________                                               Beeswax   6.0                                                                 Isopropyl alcohol                                                                       5.0                                                                 Chloroform                                                                              89.0                                                         ______________________________________                                    

EXAMPLE 14

A further alternative solution suitable for the third coating layer hasthe following percent composition by weight:

    ______________________________________                                               Kaomel ®                                                                           6.0                                                                  Methyl alcohol                                                                         29.0                                                                 Chloroform                                                                             65.0                                                          ______________________________________                                    

Kaomel^(R) is a mixture of hydrogenated vegetable oils of non-lauricorigin.

EXAMPLE 15

An alternative solution suitable for the third coating layer has thefollowing percent composition by weight:

    ______________________________________                                               Carnauba wax                                                                            5.0                                                                 Chloroform                                                                              95.0                                                         ______________________________________                                    

EXAMPLE 16

Fourth Coating (Enteric Coating)

The same operating procedure described in Example 8 for applying thesecond coating was used for the final enteric coating. The fourthcoating had the following percent composition by weight:

    ______________________________________                                        Cellulose acetate phthalate                                                                      4.0                                                        Diethyl phthalate  1.0                                                        Acetone            71.2                                                       Isopropyl alcohol  23.8                                                       ______________________________________                                    

The amount of solution used for the fourth coating depends on the amountused for the first coating. For example, 155 g of the above solution areused when 1.6 g/m² of the first coating is applied, whereas 196 g of thesame are necessary when 2.0 g/m² is used.

EXAMPLE 17

Alternatively, the fourth coating may be achieved using a solutionhaving the following percent composition by weight:

    ______________________________________                                        Cellulose acetate trimellitate                                                                    4.0                                                       Diethyl phthalate   1.5                                                       Acetone             70.0                                                      Isopropyl alcohol   24.5                                                      ______________________________________                                    

EXAMPLE 18

An alternative solution suitable for the final coating layer has thefollowing percent composition by weight:

    ______________________________________                                        Hydroxypropylmethylcellulose phthalate                                                                4.0                                                   Diethyl phthalate       1.0                                                   Acetone                 75.0                                                  Isopropyl alcohol       20.0                                                  ______________________________________                                    

EXAMPLE 19

Preparation of Controlled-Release Liquid Suspension

5.50 g microcrystalline cellulose, 0.50 g sodium carboxymethylcellulose, 0.50 g sodium citrate, 0.75 g citric acid monohydrate, 0.25 gmethyl p-hydroxybenzoate, 0.06 g propyl p-hydroxybenzoate, 0.05 g sodiumchloride, 0.02 g glycyrrhizinated ammonium and 65.77 g sugar were mixedin a mixer-granulator after sieving through a 0.4 mm average mesh. Afterdispersing 0.05 g surfactant (Span 20) and 0.20 g antifoam(dimethylpolysiloxane) in 5 ml of water, the resulting liquid was mixedwith the powder mixture and granulated in the mixer-granulator. Afterdrying to constant humidity, the resulting granulate was mixed with 1.30g tragacanth and 0.05 g powdered citrus flavoring.

25.0 g of controlled-release naproxen microgranules, obtained asdescribed in Examples 1, 5, 8, 11 and 16, were finally mixed with thevehicle granulate so as to obtain 100 g of formulation ready to besuspended in sufficient water to yield a naproxen content of 750 mg in10 ml of final suspension.

EXAMPLE 20

In Vitro Testing of Release

Release of naproxen from the formulation of the present invention wastested using apparatus II (paddle) described in the United StatesPharmacopoeia Ed. XXI operating at 50 revolutions/min in 900 ml of aphosphate buffer (pH=7.4) having the following composition:

    ______________________________________                                        Dibasic sodium phosphate dihydrate                                                                  g          14.40                                        Monobasic sodium phosphate dihydrate                                                                g           2.96                                        Demineralized water   q.s. to ml                                                                             1,000.                                         ______________________________________                                    

The active ingredient concentration was determined by measuringabsorption at 332 nm in an ultraviolet spectrophotometer. Measurementswere made directly or after separation by high performance liquidchromatography.

The release of naproxen was compared in microgranules prepared asdescribed in Examples 5 and 7. Table 1 shows the naproxen percentagesreleased by microgranules that differ from each other only with respectto the presence of polyethylene glycol in the first coatings.

                  TABLE 1                                                         ______________________________________                                        Time           % Naproxen Released                                            (Hours)        Example 5                                                                              Example 7                                             ______________________________________                                        1              41       15                                                    2              55       21                                                    4              67       30                                                    8              79       44                                                    12             85       53                                                    24             >90      65                                                    ______________________________________                                    

It is clear that, conditions being equal, the use of polyethylene glycolas one of the ingredients of the first coating ensures an optimumcontrol over the release of naproxen over 24 hours.

EXAMPLE 21

Testing of Resistance to Gastric Fluids

Testing of resistance to gastric fluids was performed using the sixvessel apparatus described in the United Stated Pharmacopoeia Ed. XXIIpage 1580. Tests were carried out at 37° C. and 60 revolutions/minute in750 ml 0.1N hydrochloric acid. Samples were taken after the first andsecond treatment hours. Microgranules prepared as described in Example 1and sequentially coated as described in Examples 5, 8, 11 and 16 werecompared with microgranules coated with a first layer of ethylcellulosewithout a superimposed enteric coating. The individual measuredpercentages of dissolved naproxen are reported in Table 2.

                  TABLE 2                                                         ______________________________________                                               % Naproxen Release                                                            Full coated     1st coat only                                          Samples  1st Hour     2nd Hour 1st Hour                                       ______________________________________                                        1        1.3          2.1      16.0                                           2        1.0          2.0      18.0                                           3        1.6          1.9      18.0                                           4        1.3          2.0      17.5                                           5        1.4          1.8      16.0                                           6        1.3          1.9      19.0                                           ______________________________________                                    

When fully coated microgranules are used, the fraction of naproxendissolved in the medium did not exceed 10% of the dose introduced; thus,the fully coated microgranules fulfill the USP XXII enteric-coatingspecification (e.g. USP Method A or USP General). By contrast, therelease profiles of microgranules lacking the enteric coating exceed theUSP limits even after the first hour.

EXAMPLE 22

Testing of Dissolution Stability With Time

Tables 3 and 4 show the stability at ambient temperature of twoformulations containing microgranules prepared as described in Example 1and sequentially coated as described in Examples 5, 8, 11 and 16, thatdiffer from each other only in the quantity of material used for coatingin relation to the surface area to be coated:

    Table 3=1.6 g/m.sup.2, Table 4=2.0 g/m.sup.2

The release of naproxen was measured as described in Example 20;measurements were taken at the time of formulation and after 30 days ofstorage at ambient temperature.

                  TABLE 3                                                         ______________________________________                                        (1.6 g/m.sup.2)                                                               Time           % Naproxen Release                                             (Hours)        Initial 30 Days                                                ______________________________________                                        1              41      42                                                     2              55      55                                                     4              67      68                                                     8              79      80                                                     12             85      85                                                     24             >90     >90                                                    ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        (2.0 g/m.sup.2)                                                               Time           % Naproxen Release                                             (Hours)        Initial 30 Days                                                1              20      22                                                     2              27      30                                                     4              38      42                                                     8              52      55                                                     12             59      60                                                     24             >80     >80                                                    ______________________________________                                    

With both formulations, the product retained unchanged releasecharacteristics even after one month. Furthermore, the larger quantityof coating applied (Table 4) considerably slowed the active ingredientrelease. For this reason, the formulation represented in Table 3 ispreferred.

EXAMPLE 23

Testing of Suspension in Vehicle

The formulation of Example 19 was tested for its ability to remain insuspension. This was done by stirring the formulation for about 30seconds, and then pouring it into a graduated cylinder and measuring theheight of the clear liquid against total liquid height at fixed times.After one hour all particles remained in suspension. After 24 hours, theheight of the clear liquid was still only 5% of the total. The presentsuspension formulation thus ensures consistency and homogeneity of anydifferent doses taken.

EXAMPLE 24

Bioavailability and Therapeutic Efficacy of Formulation

To test the bioavailability and therapeutic efficacy of the invention, akinetic study was carried out according to a cross-over design in twoperiods using single doses.

The study was conducted in 6 healthy volunteers who received a singledose (750 mg) of a liquid controlled-release naproxen formulation (A)prepared as described in Example 19 and having the followingcomposition:

    ______________________________________                                        Ingredient       Weight % Actual Weight (mg)                                  ______________________________________                                        Naproxen c.r. microgranules                                                                    25.00    937.5                                               Citric acid      0.75     31.2                                                Sodium citrate   0.50     20.8                                                Microcrystalline cellulose                                                                     5.50     230.0                                               Sodium carboxymethylcellulose                                                                  0.50     20.8                                                Tragacanth gum   1.30     54.1                                                Methyl p-hydroxybenzoate                                                                       0.25     10.4                                                Propyl p-hydroxybenzoate                                                                       0.06     2.5                                                 Sorbitan monolaurate                                                                           0.05     2.0                                                 Dimethylpolysiloxane                                                                           0.20     8.0                                                 Powdered citrus flavoring                                                                      0.05     2.0                                                 Glycyrrhizinated ammonium                                                                      0.02     0.8                                                 Sodium chloride  0.05     2.0                                                 Sugar            65.77    2840.0                                              ______________________________________                                    

In the above composition, 937.5 mg of naproxen microgranules contain 750mg of naproxen. The total weight of the above composition is 4.16 g.

For comparison, a formulation of immediate-release granular naproxen (B)having the following composition was used:

    ______________________________________                                        Ingredient      mg                                                            ______________________________________                                        Naproxen        750.0                                                         Mannitol        750.0                                                         Polyvinylpyrrolidone                                                                          75.0                                                          Methacrylic acid copolymer                                                                    112.5                                                         Sodium saccharin                                                                              52.5                                                          Lemon flavoring 150.0                                                         Citric acid     130.5                                                         Silica          7.5                                                           Sucrose         2,467.5    total weight: 4.5 g                                ______________________________________                                    

Blood samples were taken at different times and the naproxen plasmaconcentration was determined by high performance liquid chromatographyand ultraviolet spectrometry. Table 5 shows the main pharmacokineticparameters resulting from the trial.

                  TABLE 5                                                         ______________________________________                                        PHARMACOKINETIC PARAMETERS                                                    (mean values ± S.D.)                                                                 C.sub.max  T.sub.max                                                                             AUC.sub.0-∞                                          (μg.h/ml)                                                                             (h)     (μg/ml)                                       ______________________________________                                        NAPROXEN (A)                                                                              27.12        6.0     946.51                                                   (± 11.3)  (± 1.8)                                                                            (± 311.21)                                NAPROXEN (B)                                                                              76.82        2.3     1,168.58                                                 (± 18.53) (± 0.8)                                                                            (± 285.63)                                ______________________________________                                         S.D. = Standard deviation                                                     C.sub.max = (Peak concentration): the highest plasma concentration the        drug reaches after the administration;                                        T.sub.max = (Time concentration) the time necessary to reach the C.sub.ma     value;                                                                        AUC.sub.0-∞  = (Area under the curve) the total area of the             timeconcentration profile and represents a measure of the bioavailability                                                                              

The relative bioavailability (F) of two different forms (A and B)administered at the same dosage and using the same administration routeis given by the following formula:

    F=AUC(A)/AUC(B)×100.

These data show that formulation (A) reduced C_(max) considerably andextended T_(max), indicating a relative bioavailability (F) equal to 81%as compared with the reference product (B).

A literature value of 18 μg/ml, which is considered the minimum plasmalevel ensuring therapeutic efficacy Clin. Pharm. Ther. 31, 6 (1982)!,was used as a reference value to assess therapeutic efficacy. FIG. 1 isa graph showing simulated steady-state blood levels after multipleadministrations for 5 days, calculated in accordance with thepharmacokinetic parameters found. As can be seen, the present inventionis capable of maintaining therapeutic levels even with a once-dailyadministration avoiding the initial peak effect and, therefore,minimizing any occurrence of side effects associated with it.

All documents cited herein are incorporated by reference.

What is claimed is:
 1. A method of ensuring naproxen plasma levelshigher than 18 μg/ml for at least 24 hours in a patient in need of suchtreatment, comprising administering to said patient once daily acontrolled-release pharmaceutical dosage form, wherein said dosage formcomprises:a multiplicity of microgranules containing naproxen as anactive ingredient and at least one excipient, said microgranules havingsubstantially no controlled-release properties prior to coating, aseries of successive polymeric coatings that coat said microgranules,comprising: a first coating applied directly to the microgranules, atleast said first coating imparting controlled-release properties to saidmicrogranules, said coating comprising polyethylene glycol as oneingredient thereof; a second coating with hydrophilic characteristics; athird applied coating with lipophilic characteristics; and an outermostcoating with hydrophilic characteristics, at least said outermostcoating imparting resistance of said microgranules to dissolution ingastric fluids; said microgranules after coating having sizes rangingfrom 50 to 500 μm.
 2. A method as defined in claim 1, wherein saidcontrolled release dosage form is suspended in a physiologicallyacceptable aqueous medium.
 3. A method as defined in claim 1, whereinthe outermost coating of said dosage form comprises cellulose acetatephthalate as the enteric coating forming polymer and, as theplasticizer, diethyl phthalate, said diethyl phthalate being in anamount within the range from about 10% to about 30% by weight ascompared to the total weight of the second coating mixture, exclusive ofsolvents.